The present invention relates to carboxyalkylcarbonyl aminoacid inhibitors of endopeptidases useful in the treatment of cardiovascular disorders, nephrotoxicity and pain conditions.
Cardiovascular conditions which may be treated with compounds of the present invention include hypertension, congestive heart failure, edema and renal insufficiency. Nephrotoxicity resulting from immunosuppression therapy may also be treated with compounds of this invention.
Human hypertension is a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
Enkephalin is a natural opiate receptor agonist which is known to produce a profound analgesia when injected into the brain ventricle of rats. Enkephalin is known to be inactivated by a group of naturally occurring enzymes known as enkephalinases or endopeptidases.
A variety of compounds known as endopeptidase inhibitors are useful as analgesics and/or in the treatment of hypertension. For example, European Patent Application 274,234 discloses, inter alia, spiro-substituted glutaramide diuretic compounds of the formula ##STR2## wherein R.sup.5 may be a variety of alkyl or amino derivatives or a heterocycle. European Patent Application 358,398 discloses similar compounds wherein the carboxy-substituted cycloalkylamino group is replaced by a substituted alanyl group, e.g. phenylalanyl.
European Patent Application 38,046 discloses, inter alia, enkephalinase inhibitors of the formula ##STR3## wherein R.sup.2 is lower alkyl or methylthiomethyl and Ph is optionally substituted phenyl.
U.S. Pat. No. 4,513,009 discloses, inter alia, alpha amino acid derivatives of the formula ##STR4## wherein R.sup.1 is preferably hydrogen or phenyl and R.sup.2 is preferably hydrogen, alkyl, benzyl or benzyloxyalkyl. The compounds are said to have enkephalinase inhibiting and hypotensive activity.
U.S. Pat. No. 4,939,261 discloses enkephalinase inhibitory N-substituted butyramide derivatives of the formula ##STR5## wherein R.sup.1 and R.sup.2 are alkyl or arylalkyl and A is alkylene, substituted alkylene, phenylene or cyclohexylene.
U.S. Pat. No. 4,610,816 discloses, inter alia, substituted dipeptide enkephalinase inhibitors of the formula ##STR6## wherein R.sup.1 and R.sup.3 are preferably phenylethyl and R.sup.4 is preferably hydrogen, methyl or benzyl.
Similarly, German Patent Application 3,819,539 discloses, inter alia, carboxyalkyl compounds of the formula ##STR7## wherein R.sub.1 and R.sub.8 are preferably benzyl and R.sub.5 is preferably hydrogen or lower alkyl.
It has recently been discovered that the heart secretes a series of peptide hormones called atrial natriuretic factors (ANF) which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium. ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et al, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homostasis", N. Engl. J. Med., 314, 13 (1986) pp. 828-834, and M. Cantin et al in "The Heart as an Endocrine Gland", Scientific American, 254 (1986) pg. 76-81.
Angiotensin converting enzyme (ACE) inhibitors are another class of drugs known to be effective in treating some types of hypertension. ACE inhibitors are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotensin II from angiotensin I. For a review of ACE inhibitors, see M. Wyvratt et al., "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev., 5, No. 4 (1985) pp. 483-531.